How should Auvelity (dextromethorphan‑bupropion) be initiated and titrated in an adult patient with major depressive disorder who has not responded adequately to other antidepressants and has no history of seizure disorder, eating disorder, or recent MAO‑inhibitor use?

Auvelity Initiation and Titration for Treatment-Resistant Major Depressive Disorder

Start Auvelity at one tablet (45 mg dextromethorphan/105 mg bupropion) once daily in the morning for 3 days, then increase to one tablet twice daily (separated by at least 8 hours) as the maintenance dose. 1

Pre-Treatment Assessment Requirements

Before initiating Auvelity, you must complete three critical screening steps 1:

• Measure blood pressure – Auvelity can increase blood pressure and cause hypertension; baseline assessment is mandatory
• Screen for bipolar disorder, mania, or hypomania history – Risk of activation of manic episodes
• Verify no concurrent bupropion or dextromethorphan use – Avoid duplication and overdose risk

Standard Dosing Protocol

Initial Titration (Days 1-3)

• One tablet once daily in the morning
• Swallow whole – do not crush, divide, or chew 1
• This 3-day lead-in period allows tolerability assessment

Maintenance Dosing (Day 4 onward)

• One tablet twice daily
• Minimum 8-hour separation between doses
• Maximum: 2 tablets per day – never exceed this limit 1

This represents a relatively simple titration compared to most antidepressants, with therapeutic dosing achieved within 3 days. The rapid titration aligns with evidence showing clinical improvement as early as week 1 of treatment 2.

Modified Dosing for Special Populations

Moderate Renal Impairment

Remain at one tablet once daily in the morning – do not advance to twice-daily dosing 1

CYP2D6 Poor Metabolizers

Remain at one tablet once daily in the morning – these patients have impaired dextromethorphan metabolism, increasing exposure risk 1

Monitoring Schedule

Following general antidepressant guidelines, assess patient status within 1-2 weeks of initiation for therapeutic response, adverse effects, and emergence of suicidal ideation 3. The FDA mandates close monitoring for suicidal thoughts and behaviors, particularly during the first 1-2 months when risk is highest 1.

Evaluate treatment response by 6-8 weeks – if inadequate response occurs, modify treatment per standard depression management guidelines 3.

Critical Safety Contraindications

Auvelity is absolutely contraindicated in patients with 1:

• Seizure disorder (current or history)
• Bulimia or anorexia nervosa (current or prior diagnosis)
• Recent benzodiazepine, barbiturate, alcohol, or antiepileptic drug discontinuation (abrupt cessation increases seizure risk)
• MAOI use within 14 days (allow 14-day washout before starting Auvelity; wait 14 days after stopping Auvelity before starting MAOI)

Common Pitfalls to Avoid

Do not advance to twice-daily dosing before day 4 – the 3-day titration is designed for safety assessment, particularly for dizziness (a common adverse effect occurring in >5% of patients) 1.

Do not combine with other bupropion-containing products – this creates excessive bupropion exposure and dramatically increases seizure risk. Verify all current medications before prescribing 1.

Exercise caution with serotonergic agents – when used with SSRIs or tricyclic antidepressants (common in treatment-resistant depression), monitor for serotonin syndrome 1. Real-world data shows 10.7% of patients add Auvelity to an SSRI and 6.5% to an SNRI 4.

When switching from other antidepressants, consider drug interaction potential and appropriate washout periods, particularly with MAOIs 5. For ketamine or esketamine, allow for the short-to-intermediate elimination half-life before initiating Auvelity 5.

Duration of Treatment

Once adequate response is achieved, continue treatment for 4-9 months for first-episode depression 3. For patients with 2 or more prior depressive episodes, consider longer-term or indefinite maintenance therapy 3.

Clinical Context

Auvelity represents the first oral NMDA receptor antagonist approved for MDD, offering rapid onset (improvement within 1 week) compared to traditional monoamine-based antidepressants 2, 6. Real-world evidence shows 28.8% of patients initiate it as monotherapy, while 71.2% use it as add-on therapy, most commonly with SSRIs or SNRIs 4. The combination leverages bupropion's CYP2D6 inhibition to increase dextromethorphan bioavailability, creating synergistic glutamatergic and dopaminergic effects 7.

The straightforward titration schedule (3 days to therapeutic dose) and twice-daily dosing make Auvelity operationally simpler than many alternatives for treatment-resistant depression, though cost and insurance barriers may limit accessibility in practice 4, 8.